Huntington Disease: A Snapshot of New Clinical Trials

The landscape of clinical trials for Huntington disease (HD) has advanced significantly in recent years. Several potential treatment options geared toward symptom management and neuroprotection are now in development and undergoing investigation.

Neurology Learning Network’s HD Section Editor Joohi Jimenez-Shahed, MD, gives insight on some newer clinical trials of potential drug therapies for various aspects of HD. Dr Jimenez-Shahed is an associate professor of neurology and medical director of Movement Disorders Neuromodulation and Brain Circuit Therapeutics at Mount Sinai Hospital in New York.

NLN: Could you discuss the mechanism of action and previous evidence for tominersin in the treatment of HD?

Dr Jimenez-Shahed: Tominersin (also known as RO7234292) was originally developed by Ionis Pharmaceuticals, and is now being studied in clinical trials by Hoffmann-La Roche. This drug is one of an emerging class of treatments called antisense oligonucleotides (ASO), which are designed to target and lower gene products of specific messenger RNAs (mRNAs). ASOs are short nucleotide sequences that bind to a specific sequence of mRNA, causing it to be degraded and preventing it from getting translated into protein. In HD, the goal is to reduce the amount of mutated huntingtin (mHTT), which accumulates and is toxic to cells. Tominersin attaches to a segment of the mRNA that encodes this protein. 

In a phase 1/2a safety and tolerability clinical trial, tominersen was delivered intrathecally to patients with HD via lumbar puncture, and was found to reduce cerebrospinal fluid mHTT in a dose-dependent manner by up to 60%. The safety profile was favorable over 4 monthly doses. However, in a subsequent open label extension, patients were treated with 4-week or 8-week dosing, and the investigators found that over 15 months, there was sustained lowering of mHTT with both dosing regimens, but that patients tolerated the 8-week dosing much better than the 4-week dosing. This has now opened the way for a phase 3 study called GENERATION-HD1, which will look at specific efficacy measures, and is currently enrolling participants.

NLN: Could you talk about the study design for the vesicular monoamine transporter 2 (VMAT2) inhibitor valbenazine, and how this drug is different from the others in its class?

Dr Jimenez-Shahed: The KINECT-HD study is a a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of valbenazine to treat chorea among participants with HD. Patients are being randomly assigned to receive valbenazine or placebo for 12 weeks, including an 8-week titration period and a 4-week maintenance period. The primary outcome measure is the difference in the total chorea subscore of the Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score at 12 weeks compared to baseline.

Valbenazine is a VMAT2 inhibitor currently approved for treatment of tardive dyskinesia and under investigation for treatment of chorea associated with HD. VMAT2 inhibitors are described as dopamine-depleting drugs with a presynaptic mechanism of action compared to dopamine receptor-blocking drugs, which act post-synaptically and can also have antichoreic effect.

Two other drugs with this mechanism of action have already been approved for treatment of HD chorea—tetrabenazine and deutetrabenazine. Deutetrabenazine is a deuterated version of tetrabenazine, which affects metabolism such that the Cmax is lowered, potentially avoiding peak dose side effects such as somnolence and akathisia, while increasing Tmax, thereby allowing twice-daily dosing instead of the thrice-daily dosing required for tetrabenazine. Valbenazine differs because it is a prodrug of alpha-dihydrotetrabenazine, which is the active metabolite of tetrabenazine. This drug design is thought to have a favorable side effect profile and is further differentiated by once-daily dosing.

NLN: Could you discuss the rationale behind the phase 3 study for pridopidine and its design, since it has a different primary endpoint than the previous study of this drug for HD?

Dr Jimenez-Shahed: Pridopidine is a first-in-class, selective, high-affinity sigma-1-receptor (σ1R) agonist and dopamine-stabilizing compound with implications for both neuroprotection and motor benefit in HD. It was studied in the HART study, which was a randomized, double-blind, placebo-controlled clinical trial investigating the drug’s effect on the change from baseline to week 12 in the Modified Motor Score, a subset of the UHDRS Total Motor Score.

This study failed to show statistically significant changes in the primary outcome measure at a maximum dose of 45 mg twice daily. However, secondary analyses showed improvement in the Total Motor Score (TMS). The subsequent PRIDE-HD study was a randomized, placebo-controlled, phase 2, dose-ranging study to determine whether higher doses of pridopidine administered for a longer period (up to 112.5 mg twice daily delivered over 26 weeks) would reduce motor symptoms in a dose-dependent manner.

The primary endpoint was change in the UHDRS TMS from baseline to 26 weeks, but once again, a statistically significant difference among treatment groups was not seen. However, additional exploratory analyses of data from the open label extension of the HART study and the PRIDE-HD trial showed that there was an improvement in the total functional capacity (TFC) of patients treated with pridopidine 45 mg twice daily, and that the effect was more pronounced among patients with early-stage disease.

The potential for effects on maintaining TFC has prompted the design and implementation of the PROOF-HD study, a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of pridopidine 45 mg twice daily among patients with early stage HD. The primary outcome measure in this study is the change in the UHDRS-TFC  score from baseline to 65 weeks. Enrollment is currently ongoing.

NLN: What key takeaways do you hope to leave with our audience of neurologists, neurology providers, and researchers?

Dr Jimenez-Shahed: The clinical trials landscape for HD has evolved substantially over recent years. Treatment options that are now being investigated and that are in the pipeline for human study include potential symptomatic, as well as neuroprotective, agents that use a variety of biochemical approaches and drug delivery methods. The coming years will determine the degree of impact they may have on the natural history of HD.

—Christina Vogt


  1. A study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7234292 (ISIS 443139) in Huntington's Disease patients who participated in prior investigational studies of RO7234292 (ISIS 443139). identifier: NCT03342053. Updated June 9, 2020. Accessed January 11, 2021.
  2. Efficacy, safety, and tolerability of valbenazine for the treatment of chorea associated with Huntington disease (KINECT-HD). identifier: NCT04102579. Updated December 31, 2020. Accessed January 11, 2020.
  3. Pridopidine's Outcome On Function in Huntington Disease, PROOF-HD. identifier: NCT04556656. Updated November 2, 2020. Accessed January 11, 2020.